Electrocardiogram QT Research Articles

Regulation of the cardiac L-type Ca2+ channel by the actin-binding proteins alpha-actinin and dystrophin.

The actin-binding proteins dystrophin and alpha-actinin are members of a family of actin-binding proteins that may link the cytoskeleton to membrane proteins such as ion channels. Previous work demonstrated that the activity of Ca2+ channels can be regulated by agents that disrupt or stabilize the cytoskeleton. In the present study, we employed immunohistochemical and electrophysiological techniques to investigate the potential regulation of cardiac L-type Ca2+ channel activity by dystrophin and alpha-actinin in cardiac myocytes and in heterologous cells. Both actin-binding proteins were found to colocalize with the Ca2+ channel in mouse cardiac myocytes and to modulate channel function. Inactivation of the Ca2+ channel in cardiac myocytes from mice lacking dystrophin (mdx mice) was reduced compared with that in wild-type myocytes, voltage dependence of activation was shifted by 5 mV to more positive potentials, and stimulation by the beta-adrenergic pathway and the dihydropyridine agonist BAY K 8644 was increased. Furthermore, heterologous coexpression of the Ca2+ channel with muscle, but not nonmuscle, forms of alpha-actinin was also found to reduce inactivation. As might be predicted from a reduction of Ca2+ channel inactivation, a prolonging of the mouse electrocardiogram QT was observed in mdx mice. These results suggest a combined role for dystrophin and alpha-actinin in regulating the activity of the cardiac L-type Ca2+ channel and a potential mechanism for cardiac dysfunction in Duchenne and Becker muscular dystrophies.

Lack of a significant adverse cardiovascular effect of combined quinine and mefloquine therapy for uncomplicated malaria

Quinine dihydrochloride (10 mg salt/kg infused over one hour) and mefloquine (15 mg base/kg) were given simultaneously to 13 adults with uncomplicated falciparum malaria. Supine and standing blood pressures were recorded and the electrocardiogram monitored. Plasma concentrations of the 2 drugs were similar to those reported previously for the 2 compounds given individually to a similar group of patients. Although postural hypotension was common (6 cases before treatment and 7 after) and the electrocardiogram QT c interval was prolonged by a mean of 12% (SD = 8) following drug treatment, there was no evidence of a clinically significant cardiovascular pharmacodynamic interaction between these 2 structurally related antimalarial compounds.

A Cellular Model for Long QT Syndrome: TRAPPING OF HETEROMULTIMERIC COMPLEXES CONSISTING OF TRUNCATED Kv1.1 POTASSIUM CHANNEL POLYPEPTIDES AND NATIVE Kv1.4 AND Kv1.5 CHANNELS IN THE ENDOPLASMIC RETICULUM

We demonstrated that overexpression of a cRNA encoding a truncated potassium channel polypeptide that contains the NH2 terminus and the first transmembrane segment (Kv1.1N206Tag) abolished the expression of Kv1.1 and Kv1.5 outward currents in Xenopus oocytes (Babila, T., Moscucci, A., Wang, H., Weaver, F. E. & Koren, G. (1994) Neuron 12, 615-626). Recently, we showed that expression of Kv1.1N206Tag in the heart of transgenic mice resulted in the creation of mice with prolongation of the surface electrocardiogram's QT interval (London, B., Han, X., Folco, E. & Koren, G. (1996) Biophys. J. 70, A2601). To study the dominant negative mechanism of Kv1.1N206Tag, we overexpressed it in GH3 cells, a pituitary cell line expressing Kv1. 5 and Kv1.4. RNase protection analysis comparing the steady-state levels of native Kv1.5 and Kv1.1N206Tag transcripts revealed an excess of Kv1.1N206Tag transcript. Immunoprecipitation analysis using 12CA5 monoclonal antibody detected a 25-kDa polypeptide in the transfected cells. The half-life of Kv1.1N206Tag was 2.6 h. Subcellular fractionation of cell lysates labeled with [35S]methionine revealed that Kv1.1N206Tag polypeptide is detectable in the particulate (membranous) fraction, but not in the soluble (cytosol) fraction. A series of double immunoprecipitations with 12CA5 and polyclonal antibodies against Kv1.5 and Kv1.4 revealed that Kv1.1N206Tag forms heteromultimeric complexes with the native Kv1.4 and Kv1.5 polypeptides. The steady-state levels of Kv1.5 were not affected by the overexpression of Kv1.1N206Tag. Immunofluorescence colocalization and confocal microscopy analyses revealed that Kv1.1N206TagFlag did not reach the plasma membrane, and its distribution pattern was characteristic to that of a resident endoplasmic reticulum polypeptide. Our observations establish that the negative effect of Kv1.1N206Tag is mediated by the formation of heteromultimeric complexes with the native channels and by the retention of these complexes in the endoplasmic reticulum.

Electrocardiographic QTC interval: short-term weight loss effects.

Prolongation of the QTc interval is a risk-factor for ventricular arrhythmias and sudden death. There is a correlation between body mass index (BMI) and QTc, with longer intervals observed in obese subjects. Dieting and weight loss on selected diets are also associated with prolongation of the QTc interval, although the mechanisms and risk factors of this syndrome are not clearly established. The aim of the current investigation was to determine if short-term weight loss over seven days while living on a metabolic ward influences cardiac repolarization as indicated by QT interval duration. The electrocardiogram QT, RR, and QTc (QT/RR(0.5)) intervals were assessed in 30 healthy obese (BMI > 27 kg/m2) men and women ingesting a balanced 1120 kcal/d formula diet (23% kcal as fat and 52 g protein/d). Weight loss (3.9 +/- 1.7 kg) over seven days had no measurable effect on the RR interval and there was a significant (P = 0.02) shortening of the QT interval (mean +/- s.d., 0.395 +/- 0.028-0.386 +/- 0.027 s) and borderline significant (P = 0.11) shortening of the QTc (0.411 +/- 0.028-0.404 +/- 0.025 s) interval. The QTc interval normalized in three subjects with prolonged baseline QTc (> 0.44 s). A statistically significant (P = 0.007) reduction in systolic blood pressure early in the course of weight loss (day 2) accompanied the electrocardiographic changes. These results fail to support the development of cardiac repolarization abnormalities in obese patients who ingest a nutritionally balanced low calorie diet over seven days. A significant reduction in QT interval duration and amelioration of abnormally prolonged baseline QTc intervals suggest improved cardiac repolarization with early weight loss.

Serotonin and serotonin antagonism in cardiovascular and non-cardiovascular disease.

Serotonin, or 5-hydroxytryptamine, is a naturally-occurring vasoactive substance found primarily in the brain, enterochromaffin tissue, and blood platelets. It has diffuse cardiophysiologic effects. The multiple effects of serotonin on blood vessels can be explained by the existence of 2 serotonergic receptor subtypes (the S1 receptor mediates vasodilation, and the S2 receptor vasoconstriction). Serotonin via the S2 receptor also augments the actions of several other vasoconstricting substances. Serotonin may be responsible for causing, or at least perpetuating, some forms of systemic hypertension through peripheral and central nervous system (CNS) actions. Ketanserin is a highly selective S2-serotonergic antagonist with additional alpha-adrenergic blocking activity, which has been proposed as a therapy for various cardiovascular diseases including hypertension. It has been shown to be more effective than placebo in treating hypertension and comparable in effectiveness to other antihypertensive drugs. Its major side effects relate to the CNS, and prolongation of the electrocardiogram QT interval has been described. Caution must be used when using ketanserin in patients receiving potassium- and magnesium-losing agents, because of the risk of torsades de pointes. Ketanserin has potential utility in the treatment of eclampsia, peripheral vascular disease, carcinoid syndrome, and "shock lung." The drug is not yet approved for clinical use in the United States.

クラスＩＩＩ抗不整脈薬ｄ‐ｓｏｔａｌｏｌの体内動態と心電図ＱＴ時間に対する延長効果との関係

クラスＩＩＩ抗不整脈薬ｄ‐ｓｏｔａｌｏｌの体内動態と心電図ＱＴ時間に対する延長効果との関係

Reduction in QT dispersion by sotalol following myocardial infarction

Increased dispersion of ventricular recovery time is believed to be a substrate for serious ventricular arrhythmias. Class III antiarrhythmic drugs probably operate by decreasing dispersion through homogeneous prolongation of recovery time. A single surface QT value gives no information on recovery time dispersion but interlead variation in QT may be relevant. QTc dispersion was measured in 67 patients post myocardial infarction randomized to treatment with either sotalol or placebo. QTc dispersion was calculated as the difference between the maximum and minimum QTc in any surface electrocardiogram lead. Both maximum QTc and QTc dispersion varied considerably following infarction but throughout the 6-month follow-up period maximum QTc was significantly greater (P less than 0.05) and QTc dispersion significantly less (P less than 0.05) in patients on sotalol compared with placebo. These findings are in accord with expected changes in ventricular recovery time and provide strong support for the hypothesis that surface electrocardiogram QT variation reflects regional differences in ventricular recovery time.

Relationship between Plasma Calcium and QT Interval of Electrocardiogram in Dairy Cows

Relationships between calcium of blood plasma and measurements of the electrocardiogram QT interval corrected for heart rate and interval from Q to the apex of T corrected for heart rate were investigated in six dairy cows. Calcium was varied by infusing 4.7% solution of ethylenediaminetetra-acetic acid disodium salt to induce hypocalcemia, followed by treatment with calcium borogluconate. The within-cow regressions of the intervals on calcium in plasma were significant in all four electrocardiogram leads (leads I, aVF, SIII, and SaVF). These regressions differed between cows in these same leads.Correlation coefficients between calcium and the intervals were consistently larger than −.94 in lead SIII in all cows. When the results from four of the cows similar in age and breed were analyzed separately, regression coefficients between individual cows were not significantly different. However, intervals adjusted for calcium in plasma differed between cows.